Crystal structure determination and computational studies of 1,4-dihydropyridine derivatives as selective T-type calcium channel blockers

Abstract Different types of calcium channels are crucial regulators of many key physiological functions throughout the body. Therefore, calcium channel modulators are accepted as precious molecules for the therapeutic intervention of various pathologies ranging from cardiovascular to neurological diseases. 1,4-dihydropyridines (DHPs) primarily target L-type calcium channel (Cav1.2) for the treatment of hypertension and occupy a central position among all calcium channel blockers. Subsequently, T-type calcium channel Cav3.2 isoform has been established to play a significant role in chronic pain conditions. Despite the growing interest and identification of many compounds with Cav3.2 blocking activities, no molecule has passed the clinical trials and approved for the treatment of pain by now. Our group has recently identified two DHP-based molecules (HM8 and MD20) that selectively blocked T-type over L-type calcium channel. As these compounds hold great therapeutic value as potential drug candidates, we carried out further structural and computational analyses to gain insights into their various properties. Initially, the three-dimensional structure of HM8 was resolved by single-crystal X-ray analysis. The computational analysis encompassed density functional theory (DFT) and molecular dynamics (MD) simulations. DFT calculations were used to identify local reactivity properties and pharmaceutical stability, while time-dependent DFT calculations were used to simulate the UV/Vis spectra and identify the molecular parts principally responsible for the light absorption. MD simulations were used to understand the influence of water on studied molecules, and also to identify the substances that could be potentially used as excipients in pharmaceutical formulations based on HM8 and MD20.